Search Results (303)

Bisphenol A (BPA), a prevalent endocrine-disrupting chemical, is widely found in various consumer products and poses significant health risks, particularly through hormone receptor interactions, oxidative stress, and mitochondrial dysfunction. BPA exposure is associated with reproductive, metabolic, and neurodevelopmental disorders. Melatonin, a neurohormone with strong antioxidant and anti-inflammatory properties, has emerged as a potential therapeutic agent to counteract the toxic effects of BPA. This review consolidates recent findings from in vitro and animal/preclinical studies, highlighting melatonin’s protective mechanisms against BPA-induced toxicity. These include its capacity to reduce oxidative stress, restore mitochondrial function, modulate inflammatory responses, and protect against DNA damage. In animal models, melatonin also mitigates reproductive toxicity, enhances fertility parameters, and reduces histopathological damage. Melatonin’s ability to regulate endoplasmic reticulum (ER) stress and cell death pathways underscores its multifaceted protective role. Despite promising preclinical results, human clinical trials are needed to validate these findings and establish optimal dosages, treatment durations, and safety profiles. This review discusses the wide range of potential uses of melatonin for treating BPA toxicity and suggests directions for future research. Full article

Forty per cent of major depression patients are resistant to antidepressant medication. Thus, it is necessary to search for alternative treatments. Melatonin (N-acetyl-5-hydroxytryptamine) enhances neurogenesis and neuronal survival in the adult mouse hippocampal dentate gyrus. Additionally, melatonin stimulates the activity of Ca²⁺/Calmodulin-dependent Kinase II (CaMKII), promoting dendrite formation and neurogenic processes in human olfactory neuronal precursors and rat organotypic cultures. Similarly, ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, modulates CaMKII activity. Importantly, co-treatment of low doses of ketamine (10⁻⁷ M) in combination with melatonin (10⁻⁷ M) produces additive effects on neurogenic responses in olfactory neuronal precursors. Importantly, enhanced neurogenic responses are produced by conventional antidepressants like ISSRs. The goal of this study was to investigate whether hippocampal CaMKII participates in the signaling pathway elicited by combining doses of melatonin with ketamine acutely administered to mice, 30 min before being subjected to the forced swimming test. The results showed that melatonin, in conjunction with ketamine, significantly enhances CaMKII activation and changes its subcellular distribution in the dentate gyrus of the hippocampus. Remarkably, melatonin causes nuclear translocation of the active form of CaMKII. Luzindole, a non-selective MT₁ and MT₂ receptor antagonist, abolished these effects, suggesting that CaMKII is downstream of the melatonin receptor pathway that causes the antidepressant-like effects. These findings provide molecular insights into the combined effects of melatonin and ketamine on neuronal plasticity-related signaling pathways and pave the way for combating depression using combination therapy. Full article

Emerging evidence suggests a bidirectional relationship between gut microbiota, melatonin synthesis, and breast cancer (BC) development in hormone receptor-positive patients (HR+HER2+ and HR+HER2-). This study investigated alterations in gut microbiota composition, the serum serotonin–N-acetylserotonin (NAS)–melatonin axis, fecal short-chain fatty acids (SCFAs) and beta-glucuronidase (βGD) activity, and serum zonulin in HR+ BC patients compared to healthy controls. Blood and fecal samples were analyzed using mass spectrometry for serotonin, NAS, melatonin, and SCFAs; ELISA for AANAT, ASMT, 14-3-3 protein, and zonulin; fluorometric assay for βGD activity; and 16S rRNA sequencing for gut microbiota composition. HR+ BC patients exhibited gut dysbiosis with reduced Bifidobacterium longum and increased Bacteroides eggerthii, alongside elevated fecal βGD activity, SCFA levels (e.g., isovaleric acid), and serum zonulin, indicating increased intestinal permeability. Serum serotonin and N-acetylserotonin (NAS) levels were elevated, while melatonin levels were reduced, with a higher NAS/melatonin ratio in BC patients. AANAT levels were increased, and ASMT levels were decreased, suggesting disrupted melatonin synthesis. Bifidobacterium longum positively correlated with melatonin and negatively with βGD activity, while Bacteroides eggerthii showed a positive correlation with βGD activity. These findings suggested that gut microbiota alterations, disrupted melatonin synthesis, microbial metabolism, and intestinal permeability may contribute to BC pathophysiology. The NAS/melatonin ratio could represent a potential biomarker, necessitating further mechanistic studies to confirm causality and explore therapeutic interventions. Full article

Diabetic neuropathy (DN) remains a major clinical burden, characterized by progressive sensory dysfunction, pain, and impaired quality of life. Despite the available symptomatic treatments, there is a pressing need for disease-modifying therapies. In recent years, preclinical research has highlighted the potential of repurposed pharmacological agents, originally developed for other indications, to target key mechanisms of DN. This narrative review examines the main pathophysiological pathways involved in DN, including metabolic imbalance, oxidative stress, neuroinflammation, ion channel dysfunction, and mitochondrial impairment. A wide array of repurposed drugs—including antidiabetics (metformin, empagliflozin, gliclazide, semaglutide, and pioglitazone), antihypertensives (amlodipine, telmisartan, aliskiren, and rilmenidine), lipid-lowering agents (atorvastatin and alirocumab), anticonvulsants (topiramate and retigabine), antioxidant and neuroprotective agents (melatonin), and muscarinic receptor antagonists (pirenzepine, oxybutynin, and atropine)—have shown promising results in rodent models, reducing neuropathic pain behaviors and modulating underlying disease mechanisms. By bridging basic mechanistic insights with pharmacological interventions, this review aims to support translational progress toward mechanism-based therapies for DN. Full article

Recently, it has been proposed that plant melatonin receptors belong to the superfamily of G protein-coupled receptors (GPCRs). However, a detailed description of the phylogeny, protein structure, and binding properties of melatonin, which is still lacking, can help determine the signaling and function of this compound. Melatonin receptor homologs (PMTRs) were identified in 90 Viridiplantae sensu lato proteomes using profile Hidden Markov Models (HMM), which yielded 174 receptors across 87 species. Phylogenetic analysis revealed an expansion of PMTR sequences in angiosperms, which were grouped into three clades. Docking studies uncovered a conserved internal melatonin-binding site in PMTRs, which was analogous to the site in human MT1 receptors. Binding affinity simulations indicated this internal site exhibits stronger melatonin binding compared to a previously reported superficial pocket. Ligand–receptor interaction analysis and alanine scanning highlighted a major role of hydrophobic interactions, with hydrogen bonds contributing predominantly at the internal site, while non-interacting charged residues stabilize the binding pocket. Tunnel and ligand transport simulations suggested melatonin moves favorably through the internal cavity to access the binding site. Also, we presented for the first time details of these pockets in a non-model species, Capsicum chinense. Taken together, the structural analyses presented here illustrate opportunities and theoretical evidence for performing structure–function studies via mutations in specific residues within the proposed new melatonin-binding site in PMTRs, shedding light on their role in plant melatonin signaling. Full article

This study investigates the effect of monochromatic light on the body weight (BW), melatonin concentration and its receptors expression levels, intestinal health, and gut microorganisms of Yangzhou geese. Green light (GL) significantly increased BW, melatonin and its receptor expression levels, villus height (VH) and villus height/crypt depth (VH/CD) ratio, superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (T-AOC) activities, as well as the abundance of Synergistota and Prevotellaceae_UCG-001, compared with white light (WL). Blue light (BL) significantly increased the mRNA expression of melatonin membrane receptor 1a (Mel1a) and nuclear receptor 1α (RORα), VH and VH/CD ratio, CAT activity, cecal microbes diversity, and decreased malondialdehyde (MDA) levels. Red light (RL) significantly decreased average daily feed intake, reduced the abundances of Synergistota and Prevotellaceae_UCG-001, and increased Mel1a and RORα mRNA expression levels, MDA content, and cecum microbial diversity. Moreover, melatonin levels were significantly higher in the GL and BL groups compared to RL. Furthermore, the mRNA expression levels of Claudin-10, Occludin, and occludens-1 (ZO-1) were significantly upregulated under GL or BL exposures compared to the WL group, whereas RL only enhanced the expression levels of ZO-1. Spearman’s correlation analysis revealed that the relative abundance of Prevotellaceae_UCG-001 exhibited positive correlations with BW, melatonin and its receptors expression, gut health, and antioxidant capacity. Overall, these findings suggested that GL exposure enhanced melatonin synthesis and its receptors expression, modulated intestinal homeostasis and microbial ecology, and ultimately increased goose BW. Full article

Sleep disturbance is common among people with cognitive impairment and, when present, is an important target for intervention because it potentially leads to negative outcomes and cognitive decline. Given this association, sleep represents a potential public health target, although evidence for efficacy is lacking. For this study, a systematic review and meta-analysis was undertaken of controlled clinical trials of pharmacological and non-pharmacological interventions to improve sleep in mild cognitive impairment and dementia. A total of 144 trials involving 13,471 participants (median 50 per trial) were included. To measure sleep, 68 trials used subjective measures exclusively, and 41 used only objective measures, while 35 used a combination. In all, 287 discrete sleep outcome measures were reported. Bright light therapy was the most frequently examined non-pharmacological intervention, but results were equivocal. Other non-pharmacological interventions (such as physical activity, cognitive behavioural therapy for insomnia, music, and continuous positive airway pressure) showed promise but require further evidence. Results for melatonin, the most frequently examined pharmacological intervention, were inconclusive, but lower doses may be more effective. Other pharmacological interventions (such as trazadone and orexin-receptor antagonists) demonstrated effectiveness in a small number of trials but require further evidence. Overall, there is insufficient evidence upon which to base clinical decisions regarding the treatment of sleep disturbance in this population. Existing research is marked by wide heterogeneity, which limits opportunities for data synthesis. A core outcome set is urgently required to ensure that future research provides more coherent and reliable evidence to improve outcomes for people with cognitive impairment and sleep disturbance. Full article

A significant proportion of children with Autism spectrum disorder (ASD) experience sleep issues, such as insomnia and other disorders, as assessed by the Sleep Disturbance Scale for Children. Our study investigated the link between six single nucleotide polymorphisms (SNPs) in the melatonin receptor genes MT1 and MT2 and ASD susceptibility, clinical severity and associated sleep problems. A total of 139 ASD children, 82 siblings, and 53 unrelated healthy controls, all of Sardinian ancestry, were studied; among them, 38 children with co-occurring sleep issues were assessed for the outcomes of a rehabilitative program, including behavioral therapy and sleep hygiene. The MT2 rs10830963 G allele is more prevalent in ASD children and their siblings compared to the healthy controls, while rs2119882 (MT1) and rs1562444 (MT2) are associated with DIMS, DA, and SHY. ASD Children carrying the rs2119882 T allele have higher scores for DIMS and DA compared to C allele carriers, and those carrying rs1562444 A allele have higher scores for SHY than G allele carriers. After rehabilitative treatment, homozygous TT carriers of rs2119882 showed less improvement in DIMS symptoms compared to CT and CC carriers. A similar result was observed for AA carriers of SNP rs1562444 about SHY. We may suggest that the MT1 and MT2 variants may serve as useful predictive genetic markers for the severity of sleep disorders in children with ASD, potentially informing the design of more targeted rehabilitative treatments. Full article

Background: Glaucoma is a leading cause of irreversible visual loss worldwide, characterized by progressive retinal ganglion cell (RGC) degeneration and optic nerve damage. Current therapies mainly focus on lowering intraocular pressure (IOP), yet fail to address pressure-independent neurodegenerative mechanisms. Melatonin, an endogenously produced indoleamine, has gained attention for its potential in modulating both IOP and neurodegeneration through diverse cellular pathways. This review evaluates the therapeutic relevance of melatonin in glaucoma by examining its mechanistic actions and emerging delivery approaches. Methods: A comprehensive literature search was conducted via PubMed and Medline to identify studies published between 2000 and 2025 on melatonin’s roles in glaucoma. Included articles discussed its effects on IOP regulation, RGC survival, oxidative stress, mitochondrial integrity, and inflammation. Results: Evidence supports melatonin’s involvement in IOP reduction via MT receptor activation and its synergism with adrenergic and enzymatic regulators. Moreover, it protects RGCs by mitigating oxidative stress, preventing mitochondrial dysfunction, and inhibiting apoptotic and inflammatory cascades. Recent advances in ocular drug delivery systems enhance its bioavailability and therapeutic potential. Conclusions: Melatonin represents a multi-target candidate for glaucoma treatment. Further clinical studies are necessary to establish optimal dosing strategies, delivery methods, and long-term safety in patients. Full article

Type 2 diabetes mellitus represents a major global health burden and is often preceded by a prediabetic state characterized by insulin resistance and metabolic dysfunction. Mitochondrial alterations, oxidative stress, and disturbances in lipid metabolism are central to the prediabetes pathophysiology. Melatonin, a pleiotropic indolamine, is known to regulate metabolic and mitochondrial processes; however, its therapeutic potential in prediabetes remains poorly understood. This study investigated the effects of melatonin on energy metabolism, oxidative stress, and mitochondrial function in a rat model of prediabetes induced by chronic sucrose intake and low-dose streptozotocin administration. Following prediabetes induction, animals were treated with melatonin (20 mg/kg) for four weeks. Biochemical analyses were conducted to evaluate glucose and lipid metabolism, and mitochondrial function was assessed via gene expression, enzymatic activity, and oxidative stress markers. Additionally, hepatic mitochondrial dynamics were examined by quantifying key regulators genes associated with biogenesis, fusion, and fission. Prediabetic animals exhibited dyslipidemia, hepatic lipid accumulation, increased fat depots, and impaired glucose metabolism. Melatonin significantly reduced serum glucose, triglycerides, and total cholesterol levels, while enhancing the hepatic high-density lipoprotein content. It also stimulated β-oxidation by upregulating hydroxyacyl-CoA dehydrogenase and citrate synthase activity. Mitochondrial dysfunction in prediabetic animals was evidenced by the reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and mitochondrial transcription factor A, both of which were markedly upregulated by melatonin. The indolamine also modulated mithocondrial dynamics by regulating fusion and fission markers, including mitosuin 1 and 2, optic atrophy protein, and dynamin-related protein. Additionally, melatonin mitigated oxidative stress by enhancing the activity of superoxide dismutase and catalase while reducing lipid peroxidation. These findings highlight melatonin’s protective role in prediabetes by improving lipid and energy metabolism, alleviating oxidative stress, and restoring mitochondrial homeostasis. This study provides novel insights into the therapeutic potential of melatonin in addressing metabolic disorders, particularly in mitigating mitochondrial dysfunction associated with prediabetes. Full article

Insomnia is the most prevalent sleep disorder, estimated to affect at least one-third of the global population. There are a variety of treatment options available for both acute and chronic insomnia. Currently, the pharmacological arsenal for treating insomnia includes short- or intermediate-acting benzodiazepine hypnotics, non-benzodiazepine hypnotic sedatives, melatonin receptor agonists, orexin receptor antagonist, and sedating antidepressants. Diphenhydramine, a first-generation antihistamine, is commonly used in the treatment of allergies and dermatitis. This review examines the preclinical and clinical efficacy and safety evidence of diphenhydramine in treating short-term insomnia. Additionally, it provides expert consensus on its implementation as an over-the-counter medication for this condition. The available evidence indicates that diphenhydramine is an effective treatment for acute insomnia in adults, offering a safe and affordable option for most patients suffering from this condition. Experts concur that there is strong evidence supporting the recommendation of diphenhydramine for the treatment of acute insomnia in adults. Full article

Rehmannia glutinosa (RG), a fundamental herb in traditional Chinese medicine belonging to the Orobanchaceae family, has been widely used for centuries due to its diverse therapeutic properties, including promoting blood circulation, enhancing immunity, managing diabetes, reducing inflammation, and supporting kidney function. Despite its traditional significance, scientific studies on RG’s therapeutic mechanisms remain limited, and its underlying pharmacological pathways are not extensively elucidated. This study employed network pharmacology and molecular docking to identify RG’s active compounds and investigate their therapeutic potential in allergy, anemia, diabetes, and menopause. From an initial pool of 122 compounds, 50 bioactive compounds were screened based on bioavailability and drug-likeness, resulting in 40 active compounds and 11 target proteins closely associated with these conditions. Key active compounds identified included iridoid glycosides (rehmaglutin A, B, C, D, jioglutin A, B, C, jioglutolide) and other bioactive molecules such as caffeic acid, geraniol, 5-hydroxytryptamine, melatonin, and rhodioloside. Molecular docking technology was employed to verify the stable binding of target proteins with active compounds. Protein–protein interaction (PPI) analysis revealed that RG’s core target proteins are central to pathways regulating inflammation, cell survival, apoptosis, and immune response. Enrichment analyses demonstrated that RG’s target proteins intersect significantly with pathways including the AGE-RAGE signaling pathway in diabetic complications, IL-17, HIF-1 signaling, and neuroactive ligand-receptor interactions, all of which are essential in managing diabetes and menopause symptoms. These findings underscore RG’s multi-target therapeutic potential, particularly in modulating immunity, metabolism, and inflammation. This study highlights RG’s potential as a therapeutic agent and provides a framework for future research to further elucidate its mechanisms and support the development of targeted drugs based on RG’s active compounds. Full article

Background/Objective: The single-nucleotide polymorphism (SNP) rs10830963 in the melatonin receptor 1B (MTNR1B) gene influences insulin secretion and glucose metabolism and has been associated with an increased risk of type-2 diabetes. This study aimed to explore the interaction between dietary intake and the MTNR1B rs10830963 polymorphism on glycemic profiles in young Brazilian adults. Methods: This cross-sectional study assessed 200 healthy young adults (19–24 years), evaluating the MTNR1B rs10830963 genotype, anthropometric parameters, glycemic markers (fasting insulin, glucose, HOMA-IR, and HOMA-β), and dietary intake via three 24 h dietary recalls. Genotype–diet interactions were tested using multivariate linear regression models adjusted for confounders. Results: The carriers of the G allele exhibited a positive association with fasting insulin levels (p = 0.003), insulin/glucose ratio (p = 0.004), HOMA-IR (p = 0.003), and HOMA-β (p = 0.018). Energy-adjusted fiber intake showed a significant genotype-specific interaction only in carriers of the G allele, where higher dietary fiber intake was significantly associated with lower fasting insulin (p_interaction = 0.034) and HOMA-IR (p_interaction = 0.028). Conclusion: Our findings indicate that the MTNR1B rs10830963 polymorphism is associated with glycemic markers, and dietary fiber intake may attenuate the adverse effects of the MTNR1B rs10830963 G allele on glycemic profiles in young Brazilian adults. This highlights the potential role of fiber in improving health outcomes for individuals carrying this risk allele. To validate these results and assess the broader implications for the Brazilian population, further intervention studies and larger-scale research are essential. Full article

Circadian rhythms are molecular oscillations governed by transcriptional–translational feedback loops (TTFLs) operating in nearly all cell types and are fundamental to physiological homeostasis. Key circadian regulators, such as circadian locomotor output cycles kaput (CLOCK), brain and muscle ARNT-like 1 (BMAL1), period (PER), and cryptochrome (CRY) gene families, regulate intracellular metabolism, oxidative balance, mitochondrial function, and synaptic plasticity. Circadian disruption is known as a central contributor to the molecular pathophysiology of neurodegenerative disorders. Disease-specific disruptions in clock gene expression and melatoninergic signaling are known as potential early-stage molecular biomarkers. Melatonin, a neurohormone secreted by the pineal gland, modulates clock gene expression, mitochondrial stability, and inflammatory responses. It also regulates epigenetic and metabolic processes through nuclear receptors and metabolic regulators involved in circadian and cellular stress pathways, thereby exerting neuroprotective effects and maintaining neuronal integrity. This review provides recent findings from the past five years, highlighting how circadian dysregulation mediates key molecular and cellular disturbances and the translational potential of circadian-based therapies in neurodegenerative diseases. Full article

A key feature in sheep biology is reproduction seasonality which concerns the cyclical occurrence of natural breeding, which therefore does not take place throughout the year. Since sheep are short-day breeders, the amount of daylight has an impact on their reproductive activity. The melatonin receptor subtype 1A (MTNR1A) gene is the primary gene that has been linked with seasonality. Nonetheless, information regarding the potential genetic association between other loci and the seasonality of sheep reproduction is scarce. Genome-wide association study (GWAS) is considered a cutting-edge methodology for comprehending the genetic architecture of complex traits since it enables the discovery of many markers linked to different features. In the present study, three indigenous Greek sheep breeds were investigated using GWAS—two of which presented strict patterns of reproduction seasonality, i.e., the Florina and Karagkouniko breeds, while the third one, i.e., the Chios breed had the ability to exhibit estrus throughout the year—in an attempt to detect the genetic loci linked with reproduction seasonality. All three breeds of investigated animals were purebred with Chios and Florina breeds originating from the Greek national stationary stock, whereas Karagkouniko originated from a commercial farm. Interestingly, a significant genetic differentiation of the national stationary stock groups was suggested by principal component analysis, phylogenetic analysis, and admixture and spatial point patterns, with these two breeds being less heterogeneous. This finding highlights the value of stationary stocks towards the maintenance of genetic integrity in indigenous sheep, demonstrating the Greek station’s critical role in the conservation of native sheep breeds. On the other hand, according to the GWAS data analysis, no genetic loci were correlated with reproduction seasonality, emphasizing the MTNR1A gene as the main determinant of the seasonality in native non genetically improved breeds. Full article